Osteoporosis is a progressive and debilitating metabolic bone disease characterized by low bone mass (bone loss) and structural deterioration (thinning of the cortical bone and disorganization of the trabecular bone) leading to increased bone fragility and susceptibility to fractures especially of the hip (femoral head), spine (vertebrae) and the wrist. Osteoporosis is a ‘silent’ disease because related bone loss occurs without symptoms until the individual suffers a bone fracture. Worldwide, the number of hip fractures due to osteoporosis was projected to rise from 1.7 million in 1990 to 6.3 million by 2050. In the U.K., it was estimated that the National Health Service cost associated with osteoporosis is over L600 million ($1.02 billion) per year in 1991 and projected to increase considerably. In Japan, estimated number of hip fracture in 1998 was about 90,000/year with associated hospital cost of about $120 million per year. In the U.S., osteoporosis is responsible for more than 1.5 million fractures/year including: 300,000 hip fractures and approximately 700,000 vertebral fractures, 200,000 wrist fractures and 300,000 fractures in ribs and other sites. 12% to 20% of patients with hip fracture die within a year after the fracture, usually from complications related to either the fracture or surgery. In 2001, the estimated health care cost (hospitals and nursing homes) related to osteoporosis and associated fractures were $17 billion ($47 million/day!) and projected to increase to $30 to $40 billion annually in the next decade.
Bone tissue consists of two types: cortical (or compact bone) and trabecular (or spongy bone), differing in architecture, properties and function. The cortical bone provides mechanical strength and protective functions while cancellous or trabecular bone provides the metabolic functions. Two major processes are responsible for the development and maintenance of the bone tissue: bone formation (bone build-up) and bone resorption (bone modeling). During skeletal development in humans (birth to adulthood), the rate of bone formation is much greater than the rate of bone resorption until maximum bone mass (peak bone mass) is reached (at about age 35 for cortical bone and earlier for trabecular bone). After the peak bone mass is reached, the bone turnover per year is about 25% in trabecular bone and 3% in cortical bone. A bone remodeling process (bone turnover) in which the rates of bone formation and bone resorption are equal in the same site maintains the skeletal mass in adulthood. When these two processes are in equilibrium or are “coupled,” there is no net gain or loss in bone mass. It is believed that the bone loss associated with primary type of osteoporosis results from the uncoupling of these two processes; with the rate of bone formation being much lower than the rate of resorption. A secondary type of osteoporosis is observed after prolonged immobilization and prolonged periods of bed rest or under glucocorticoid treatment for pulmonary disorders. In such conditions the mechanism of bone loss include both increased bone resorption and decreased bone formation. Reduction in bone formation leads to inadequate bone replacement during remodeling and to gradual bone loss resulting in the thinning of the cortical bone and reduction in cancellous bone formation.
Two major bone cells are involved—osteoblasts for bone formation and osteoclasts for bone resorption. Bone formation is reflected in osteoblast activities involving matrix (collagen, protein, DNA) formation and mineralization. Bone resorption is determined by the rate of osteoclast recruitment and the intensity of osteoclast activity manifested by the appearance of resorption pits. Most conditions leading to osteoporosis (including estrogen deficiency, hyperparathyroidism and hyperthyroidism) are associated with increased osteoclastic bone resorption and the inability of the bone formation process to keep up with the resorption process.
Bone is a composite of about 25 wt % biopolymer (organic matrix), 70 wt % mineral or inorganic phase, and 5 wt % water. The organic matrix is principally (about 95%) of Type I collagen with non-collageneous proteins. Osteoporosis is characterized by bone loss, decreased bone strength, lower bone density, poorer bone quality (e.g., porous cortical bone), thinning cortical bone and disorganized trabecular bone. Bone loss is often a predictor of future fracture risk.
In bone resorption, dissolution of the bone mineral occurs before the degradation of the collagen fibers. The rate of osteoclastic destruction of mineralized tissues was observed to be inversely proportional to bone mineral density. The bone mineral or inorganic component of bone is a calcium phosphate idealized as a calcium hydroxyapatite, Ca10(PO4)6(OH)2. However, comprehensive studies on synthetic and biologic apatites demonstrate convincingly that biologic apatites (mineral phases of enamel, dentin, cementum and bone) are apatites containing minor constituents (carbonate and magnesium) and are more accurately described as carbonate hydroxyapatite, approximated by the formula, (Ca,Na,Mg)10(PO4,HPO4,CO3)6(OH)2. Changes in the composition of the apatite affect its lattice parameters, morphology, crystallinity (reflecting crystal size and/or perfection) and dissolution properties. For example, Mg-for-Ca or CO3-for-PO4 substitution decreases crystallinity (crystal size) and increases solubility while F-for-OH substitution increases crystal size and decreases the solubility of synthetic apatites.
Osteoporotic bones were observed to have lower magnesium (Mg) and carbonate (CO3) concentrations. Along with decreased Mg and CO3 contents, larger bone apatite crystals (based on infrared spectroscopic measurements of ‘crystallinity index’) were reported in bones from patients with postmenopausal osteoporosis and alcoholic osteoporosis. Smaller bone apatite crystals were observed in bones of rats fed excess Mg while bone apatite crystals increased in size in bones from Mg-deficient rats. Enamel crystals of rats injected with Mg were smaller than those of the controls. On the other hand, bone apatite crystals from rats drinking high levels of fluoride (F) were larger and less soluble. Increase in width of bone apatite crystals were also observed in the bones of F-treated rabbits. Larger enamel apatite crystals in rat's teeth were observed after F administration.
Although there is still no known cure for osteoporosis, some medications have been approved by the FDA for postmenopausal women to prevent and/or treat osteoporosis. These include biphosphonates such as alendronate (Fosamax) and Risedmate (Actonel), Calcitonin (e.g., Miacalcin), estrogen (e.g., Climara, Estrace, Estraderm, Estratab, Ogen, Orto-Es, Viovlle, Premarin, etc) and hormones (estrogens and progestins (e.g., Activella, FemJHrt, Premphase, Prempro, etc); and selective estrogen receptor modulators, SERMs such as ralozifene (Evista). Sodium fluoride (NaF) treatment is pending approval. Treatments under investigation include parathyroid hormone (PTH), vitamin D metabolites, other biphosphonates, and SERMs. These therapeutic agents, except F therapy, are described as anti-resorptive agents because they principally target bone resorption. These therapeutic agents are associated with some serious side effects. For example, estrogen therapy is associated with cancer while bisphosphonate-based drugs are associated with osteonecrosis of the jaw and delayed healing.
Currently, experimental fluoride compounds recommended for osteoporosis therapy include sodium fluoride (NaF), monosodiumfluorophosphate, MFP, (Na2PO3F) and slow release preparation of NaF (SR—NaF). There is general agreement that F stimulates bone formation directly without the need for prior bone resorption and that it is this uncoupling of resorption and formation that makes this element so effective in increasing bone mass. However, fluoride therapy has also been associated with increased fracture risk despite increased bone mass.
The bone mineral can best be described as a carbonate hydroxyapatite, approximated by the formula: (Ca,Na,Mg)10(PO4,CO3,HPO4)6 (OH,Cl)2 containing about 40% calcium. Calcium is stored in bone in the process of mineralizing newly deposited tissue and it is withdrawn from bone only by resorption of old bone tissue. The biological fluids are metastable with respect to apatite, maintaining the integrity of the bone and tooth mineral (apatite). Ca deficiency in the diet induces osteoporosis in rats. Ca supplementation is strongly recommended for optimum bone health. Ca supplementation has been reported to reduce cortical bone loss during the first 5 years of menopause and produce a sustained reduction in the rate of total body bone loss at least 3 years after menopause. However, by itself, Ca supplementation does not appear to slow the rapid loss of trabecular bone during the first few years of menopause nor does it prevent the menopause-related lumbar bone loss. A study on spinal bone loss in postmenopausal women supplemented with Ca and trace minerals (zinc, manganese and copper) showed that bone loss was arrested by intake of Ca plus trace minerals while no difference was observed between the placebo group or group receiving Ca alone.
Magnesium (Mg) is an important element in biological systems. 50% to 60% of Mg in the body is associated with the bone mineral. The rest of the Mg in the body is intracellular, a required co-factor in more than 300 enzyme systems. Mg is critical for cellular functions that include oxidative phosphorylation, glycolysis, DNA transcription and protein and nucleic acid synthesis. Mg deficient diet in rats was shown to have impaired bone growth (reduction in bone formation and bone volume), decreased bone strength and increased fragility. These and other animal studies implicate Mg deficient diet as a possible risk factor for osteoporosis. In humans, Mg deficiency in the diet was also associated with osteoporosis. Mg therapy was reported to increase bone mass in postmenopausal osteoporosis. Other studies suggest that Mg supplementation suppresses bone turnover rates in young adult males. On the cellular level, in vitro, an isolated report indicates that Mg directly stimulated osteoblast proliferation.
Zn is an essential trace element in the activity of more than 300 enzymes and affects basic processes of cell division, differentiation, and development and is required in collagen biosynthesis and in the biosynthesis and repair of DNA, in matrix and protein synthesis and plays an important role in bone metabolism and growth. It is the most abundant trace metal in bone mineral, being present at a concentration of up to 300 ppm. Zn deficiency in rats was shown to result in a 45% reduction in cancellous bone mass and to a deterioration of trabecular bone architecture, with fewer and thinner trabeculae and therefore may be considered as a risk factor in the development of osteoporosis. In vivo, Zn was shown to stimulate bone formation in weanling rats and in aged rats.
On the cellular level in vitro, Zn has been shown to have a stimulatory effect on bone formation and an inhibitory or biphasic effect on osteoclastic bone resorption. Studies on Zn-releasing compounds such as b-alanyl-L-histadanato zinc and Zn-TCP demonstrated that Zn promoted greater bone formation in vitro and was effective in increasing bone density or in preventing bone loss in vivo.
On the crystal level in synthetic systems, the presence of Zn causes the formation of apatite with low crystallinity, promoting the formation of Zn-substituted .β-TCP or even amorphous calcium phosphate (ACP), depending on the solution Zn/Ca molar ratio. Both Mg and Zn were shown to inhibit the growth of apatite.
The relevant literature suggests that Mg or Zn separately may have beneficial effects on bone matrix but may cause the formation of bone apatite with low crystallnity (small crystal size). On the other hand, F may improve crystallinity (larger crystal size) and reduce solubility of bone apatite, but may cause impaired or abnormal mineralization. Separately, Mg, Zn and F ions have been associated with promotion of osteoblastic activity (bone formation) and/or inhibition of osteoclastic activity (bone resorption). Zn-releasing compounds, such as b-alanyl-l-histadano zinc compounds and Zn-TCP have been shown to have therapeutic effect on osteoporosis in rats induced by zinc-deficiency. Mg and Zn deficiencies have been reported as risk factors for osteoporosis. F compounds (NaF, monofluorophosphate and slow-releasing NaF) are used in the management of osteoporosis.